Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Abstract

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

Figure 1. Signal plots of the trans-ethnic “discovery” GWAS meta-analysis for novel T2D susceptibility loci

The trans-ethnic meta-analysis comprises 26,488 T2D cases and 83,964 controls from populations of European, East Asian, South Asian, and Mexican and Mexican American ancestry, imputed up to 2.5 million Phase II/III HapMap autosomal SNPs. Each point represents a SNP passing quality control in the trans-ethnic meta-analysis, plotted with their p-value (on a −log₁₀ scale) as a function of genomic position (NCBI Build 36). In each panel, the lead SNP is represented by the purple symbol. The colour coding of all other SNPs indicates LD with the lead SNP (estimated by CEU r² from Phase II HapMap): red r²≥0.8; gold 0.6≤r²<0.8; green 0.4≤r²<0.6; cyan 0.2≤r²<0.4; blue r²<0.2; grey r² unknown. The shape of the plotting symbol corresponds to the annotation of the SNP: upward triangle for framestop or splice; downward triangle for non-synonymous; square for synonymous or UTR; and circle for intronic or non-coding. Recombination rates are estimated from Phase II HapMap and gene annotations are taken from the University of California Santa Cruz genome browser.

Figure 2. Signal plots presenting 99% credible sets of SNPs at the JAZF1 and SLC30A8 loci

The credible sets were constructed on the basis of: (i) the meta-analysis of European ancestry GWAS only (12,171 cases and 56,862 controls); and (ii) the trans-ethnic meta-analysis of European, East Asian, South Asian, and Mexican and Mexican American ancestry GWAS (26,488 cases and 83,964 controls). In each panel, each point represents a SNP passing quality control in the MANTRA analysis, plotted with their Bayes’ factor (on a log₁₀ scale) as a function of genomic position (NCBI Build 36). The lead SNP is represented by the purple symbol. The colour coding of all other SNPs indicates LD with the lead SNP (estimated by Phase II HapMap CEU r² for the European ancestry meta-analysis and CHB+JPT for the trans-ethnic meta-analysis to highlight differences in structure between ancestry groups): red r²≥0.8; gold 0.6≤r²<0.8; green 0.4≤r²<0.6; cyan 0.2≤r²<0.4; blue r²<0.2; grey r² unknown. The shape of the plotting symbol corresponds to the annotation of the SNP: upward triangle for framestop or splice; downward triangle for non-synonymous; square for synonymous or UTR; and circle for intronic or non-coding. Recombination rates are estimated from Phase II HapMap and gene annotations are taken from the University of California Santa Cruz genome browser. The genomic region covered by the 99% credible set is highlighted in grey.